NADPH oxidase-derived superoxide anion mediates angiotensin enhanced carotid body chemoreceptor sensitivity in heart failure rabbits

Objective: A previous study from this laboratory showed that elevation of endogenous angiotensin II (Ang II) and upregulation of the angiotensin 11 type I (AT,) receptor in the carotid body (CB) ire involved in the enhanced peripheral chemoreceptor sensitivity in rabbits with chronic heart failure (CHF). NADPH oxidase-derived superoxide anion mediates the effects of Ang 11 in many organs. We investigated whether this signaling pathway may mediate the enhanced peripheral chemoreceptor sensitivity induced by Ang 11 in CHF rabbits. Methods and results: By recording single-unit activity from the carotid sinus nerve in isolated preparations, we found that phenylarsine oxide 2 mu M (PAO, NADPH oxidase inhibitor) and TEMPOL 1 mM (superoxide dismutase mimetic) significantly decreased not only the Ang II-enhanced CB chemoreceptor responses to different levels of hypoxia in sham rabbits (Delta-12.5 +/- 0.8 and Delta-12.8 +/- 0.9 imp/s at 40.7 +/- 2.3 mm Hg of PO2, and Delta-5.6 +/- 0.5 and Delta-5.3 +/- 0.4 imp/s at 60.2 +/- 3.1 mm Fig Of PO2, p < 0.05, respectively) but also the CHF-induced elevation of CB chemoreceptor responses to different levels of hypoxia (Delta-13.6 +/- 1.1 and Delta-13.7 +/- 0.9 imp/s at 40.9 +/- 3.1 mm Fig Of PO2, and Delta-6.7 +/- 1.2 and Delta-6.6 +/- 0.8 imp/s at 59.8 +/- 3.5 min Fig Of PO2, p < 0.05). I addition, mRNA and protein expressions of NADPH oxidase components (gp91(phox), p40(phox) and p47(phox)) were higher in the CB from CHF rabbits compared to sham rabbits. Furthermore, 100 pM Ang II induced an increase in superoxide production in CB homogenates from sham rabbits, which was similar to that in CB homogenate from CHF rabbits. PAO and Tempo] inhibited the Ang II- and CHF-enhanced superoxide anion production. Conclusions: These results suggest that the enhanced peripheral chemoreceptor sensitivity mediated by Ang 11 in CHF rabbits occurs via a NADPH oxidase-superoxide signaling pathway. (c) 2007 European Society of Cardiology. Published by Elsevier B.V All rights reserved.